ABSTRACT A syndrome of delayed anaphylaxis to mammalian meat, now commonly referred to as the α-Gal syndrome (AGS), was first reported in 2009 in a cluster of cases in the southeastern United States. The reactions were related to IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (α-Gal), an antigen of non-primate mammals which is the target of IgM, IgG and IgA antibodies in healthy humans. Over the past ten years it has become increasingly clear that tick bites, particularly bites from the lone star tick (Amblyomma americanum), are the dominant cause of IgE sensitization to α-Gal and that AGS cases are not rare, nor limited to small geographic areas of the United States. Based largely on cases investigated in allergy clinics, AGS is understood to manifest with hives and/or anaphylaxis 3-6 hours after ingestion of mammalian meat, with many patients also reporting concomitant gastrointestinal (GI) symptoms. Increasingly, however, we and other providers in our area recognize patients who are sensitized to α-Gal that report isolated GI symptoms which are triggered by mammalian meat and dairy. We are also seeing many α-Gal sensitized patients who carry a diagnosis of irritable bowel syndrome (IBS), but who have responded favorably to a diet free of mammalian meat and dairy. These observations, coupled with the fact that the population prevalence of α-Gal sIgE sensitization is upwards of 15% in many parts of the Southeast, raise the question of whether AGS could be an important and unrecognized cause of IBS-like presentations in our region. The goal of this proposal is to further investigate this possibility and also to seek a better understanding of the biological factors that affect whether an α-Gal sensitized subject will present with severe anaphylaxis, more mild IBS-spectrum GI complaints or, in some cases, no symptoms whatsoever. Recognition of such biological factors could impact AGS management by leading to improved tools for risk stratification and open up novel therapeutic strategies. To achieve the study objectives we will carry out a population-based study focusing on subjects that are expected to be high- risk for α-Gal sensitization. In contrast to most other studies of AGS, which have selectively enrolled patients who have presented to allergy clinics, here we will recruit subjects with recent tick bites from the community without regard to their allergic history. This approach will help address open questions about the frequency and presentation of AGS among those who are sensitized to α-Gal. Clinical and immunologic features of these subjects will be compared with features of AGS patients who seek care in our allergy clinic. We will also employ a novel quantitative immunoassay to address the idea that patients who have less severe manifestations of AGS have higher relative levels of anti-α-Gal IgG or IgA antibodies.